ETHNOPHARMACOLOGICAL RELEVANCE: Siwei Jianghuang Decoction (SWJHD), a renowned Tibetan medicine formula in China, has the effect of balancing "three factors" and serves as a viable therapeutic option for managing diabetes mellitus and its complications, including diabetic nephropathy (DN). However, the underlying mechanism behind its therapeutic actions remains to be fully elucidated. AIM OF THE STUDY: The current study was designed to investigate the protective effects of SWJHD on renal tissues of rats with high fat and high glucose diet (HFD) and streptozotocin (STZ)-induced DN. Additionally, it explored the mechanism of SWJHD in combating oxidative stress, inflammation and apoptosis via inhibition of the NOX-4/NF-κB/MCP-1 pathway. MATERIALS AND METHODS: Firstly, the representative components in the water extract of SWJHD were detected using HPLC. The beneficial effects of SWJHD were analyzed by examining FBG levels, renal function indicators (such as Scr, BUN, and urinary protein levels), pathological changes, oxidative stress markers, and inflammatory cytokines, and apoptosis-related indicators in renal tissues of DN rats following gavage with different SWJHD doses (0.63 g/kg and 1.26 g/kg). Subsequently, molecular docking was utilized to discover the potential associations between representative components of SWJHD and oxidative stress/apoptosis-related proteins. Furthermore, the expression levels of genes and proteins in renal tissues, including NOX-4, NF-κB, MCP-1, Bax, Bcl-2, Cyto-c, and cleaved Caspase3 were estimated by PCR, immunofluorescence analyses, and Western blot. RESULTS: Phytochemical profiling demonstrated that curcumin, berberine, palmatine, jatrorrhizine, ellagic acid, magnoflorine, and gallic acid were principally representative ingredients in SWJHD. The results confirmed that SWJHD administration attenuated DN, as evidenced by decreased levels of FBG, MDA, MPO, TNF-α, IL-1β and IL-6. It also effectively improved OGTT, increased the levels of GSH, GSH-PX, and SOD, as well as reduced the abnormal renal index, ameliorated renal histopathology and ultrastructure, and reduced the number of apoptotic cells in the kidney. The molecular docking results indicated that the principal constituents of SWJHD and proteins related to oxidative stress, inflammation, and apoptosis had potentially reactive sites. Additionally, SWJHD treatment suppressed the expression of NOX-4, MCP-1, and NF-κB genes and proteins. Meanwhile, SWJHD significantly reduced the apoptosis, inhibited the up-regulation of Bax, Cyto-c, and cleaved Caspase-3 at both the gene and protein levels, and increased in the level of Bcl-2 in the retinal tissues of DN rats. CONCLUSIONS: SWJHD may afford a protective intervention in DN rats by suppressing the oxidative stress, inflammation and apoptosis via inhibition of the NOX-4/NF-κB/MCP-1 pathway.